The adult respiratory distress syndrome (ARDS) is a common and often fatal complication of septic shock (see Fowler, A. A., et al. (1983), "Adult respiratory distress syndrome: Risk with common predispositions." Ann. Int. Med. 98, 593-597, and Fein, A. M., et al. (1983), "The risk factors, incidence, and prognosis of ARDS following septicemia," Chest 83, 40-42). Several cellular and humoral factors have been implicated in the pathogenesis of ARDS, including neutrophils, platelets, fibrin, arachidonic acid metabolites, serotonin, histamine and C5a (see Stevens, J. H. and T. A. Raffin (1984), "Adult respiratory distress syndrome--I. Etiology and mechanisms." Post. Med. J. 60, 505-513). Recent reports have suggested that C5a mediates neutrophil attraction, aggregation, activation and subsequent pulmonary endothelial damage thus being a critical component in the pathogenesis of ARDS (see Tate, R. M. and J. E. Repine (1983), "Neutrophils and the adult respiratory distress syndrome: State of the art." Am. Rev. Resp. Dis. 128, 802-806; Sacks, T., et al. (1978), "Oxygen radicals mediate endothelial cell damage by complement stimulated granulocytes. An in vitro model of immune vascular damage." J. Clin. Invest. 61, 1161-1167; and Craddock, P. R., et al. (1977), "Complement (C5a)-induced granulocyte aggregation in vitro: A possible mechanism of complement-induced leukostastis and leukopenia." J. Clin. Invest. 60, 260-264). This sequence of events may be the primary pathogenetic mechanism for the development of ARDS in septic shock (see Stevens, J. H. and T. A. Raffin (1984), "Adult respiratory distress syndrome--I. Etiology and mechanisms." Post. Med. J. 60, 505-513). In vitro studies have demonstrated that C5a generated from endotoxin or zymosan-activated plasma causes neutrophil aggregation (see Hammerschmidt, D. E., et al. (1980), "Granulocyte aggregometry: A sensitive technique for the detection of C5a and complement activation." Blood 55, 898-902). In addition, C5a-activated neutrophils are more adherent and are cytopathic to endothelial cells in tissue culture (see Tonnesen, M. G., et al. (1984), "Neutrophil-endothelial cell interactions: Modulation of neutrophil adhesiveness induced by complement fragments C5a and C5a des Arg and formyl-methionyl-leucyl-phenylanaline in vitro. J. Clin. Invest. 74, 1581-1592).
In vivo studies investigating mice which are genetically deficient in C5 have established that C5 is required for pulmonary edema formation in response to pneumococcal sepsis, scald wounds and hyperoxia (see Hosea, S. F., et al. (1980), "Role of complement activation in a model of adult respiratory distress syndrome." J. Clin. Invest. 66, 375-382; Gelfand, J. A., et al. (1982), "Alternative complement pathway activation increases mortality in a model of burn injury in mice." J. Clin. Invest. 70, 1170-1176; and Parrish, D. A., et al. (1984), "Pulmonary response of fifth component of complement-sufficient and-deficient mice to hyperoxia." J. Clin. Invest. 74, 956-965). When patients at high risk to develop ARDS were followed prospectively, detection of an elevated C5a was a useful predictor of the onset of ARDS (see Hammerschmidt, D. E., et al. (1980), "Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome: Pathophysiological relevance and possible prognostic value." Lancet 1, 947-949). A prospective study of 40 patients with sepsis (P. S. Weinberg, et al. (1984), Am. Rev. Respir. Dis. 130, 791-796) found levels of C5a des Arg and C3a des Arg were elevated in nearly all of the patients. Also within this patient population 60% had severe lung injury and 25% had ARDS.
The present invention provides a novel means of treating ARDS and sepsis which comprises administration of antibody to complement factor C5a.